The control of infection acquired in a clinical setting is a major and significant health care problem. Infections contracted during patient treatment within healthcare facilities have been estimated to contribute to ninety-thousand (90,000) deaths and cost $12 Billion dollars U.S. to treat per annum.
Nosocomial bacteriuria is the most common infection contracted in long-term care facilities and is usually associated with catheterization. The condition is virtually universal in patients after thirty days of catheterization. Complications will include fever, acute and chronic pyelonephritis, bacteremia and renal stones. The extra-lumenal surface of the catheter may become colonized with bacteria and act as a conduit for bacterial entry into the bladder. The best preventative measure is to limit the use of long-term in-dwelling catheters; this is often not possible. J. W. Warren, "Management of patients in long-term care facilities with catheter-associated bacteriuria" Infect. Urol. 9, 147-152 (1996). However, all patients will develop bacteriuria if catheterized for a long enough period.
Catheter-related septicemia occurs in approximately 400,000 of the estimated five million Americans who are catheterized each year. Treatment for a single event of catheter-related septicemia in a critically ill patient adds approximately 6.5 days to a stay in an intensive care unit and will cost about $29,000. I. R. Raad and R. O. Darouchie, "Catheter-related septicemia: risk reduction." Infect Med 13:807-812, 815-816, 823 (1996). Indeed, catheter-related septicemia represents the most common life-threatening complication associated with intravascular catheters. There is a strong relationship between catheter-site inflammation and the recovery of bacteria from the surface of the device. In situ, the catheter surface becomes colonized with opportunistic microbial pathogens, and these colonies become the source of infections.
A common source for catheter colonization and catheter-related sepsis is the skin insertion site. Indeed, the skin surface is the most common source of short-term catheter colonization and subsequent infection. Catheter-related infections remain a significant problem in healthcare facilities. It is generally accepted that no method has yet emerged for the adequate and satisfactory management of catheter-related infection.
The adhesion of microorganisms to the catheter surface is related to the interaction of the host, the microorganisms and the catheter material. The host tissue reacts to the catheter material as a foreign body and deposits a thrombin coat over the material, which becomes colonized with microbes, often within 24 hours; this coating of protein and microorganisms is called a biofilm. In the biofilm, microbes find a suitable niche for continued growth as well as for protection from antibiotics, phagocytic neutrophils, macrophages and antibodies.
There have been numerous attempts to produce biomedical products that impede or prevent infection. Biomedical products that incorporate and release silver compounds for infection control have been studied for many years. However, clinical studies of these products, including catheters, have shown only minor improvements in infection control. The devices have been described to exhibit resistance to infection, but in practical application fail to adequately inhibit infection.
Ciresi et al. 1996 (Am Surg 62:641-646) compared the incidence of catheter-related infection and catheter-related sepsis between a standard catheter and the recently released Arrowgard.TM. catheter in a clinical trial with one-hundred-ninety-one patients receiving total parenteral nutrition. The Arrowgard.TM. catheter contains a combination of silver sulfadiazine and chlorhexidine, that is thought to render the catheter surface resistant to bacterial colonization and subsequent sepsis. The authors concluded that the coating of the central venous catheters with sulfadiazine and chlorhexidine does not reduce the rate of catheter-related infection or catheter-sepsis when compared with a standard central venous catheter in patients receiving total parenteral nutrition.
Hasaniya et al. 1996 (Chest 109:1030-1032) found that the use of an attachable subcutaneous silver-impregnated cuff failed to decrease the incidence of central venous catheter-related infection and sepsis.
In U.S. Pat. No. 4,442,133 there is disclosed a process for vascular prostheses with a cationic surfactant, e.g. tridodecylmethyl-ammonium chloride (TDMAC), to increase sites for antibiotic bonding. Before the prostheses are used they are dipped or coated in a solution of TDMAC to adsorb the antibiotic.
Stickler et al. 1994 (Cells and Materials 4:387-398), conclude that pretreatment by adventitious coating of catheters with ciprofloxacin (an antibiotic) is unlikely to prevent bacterial biofilm formation on long-term, in-dwelling silicone or silicone-coated latex urethral catheters.
U.S. Pat. No. 4,749,585 provides a method for coating a prosthesis with an ionically charged surfactant and an antibiotic compound encapsulated within phospholipid vesicles, wherein said vesicles have a surface charge opposite to that of said surfactant. The drawback of this system is that the amount of liposomes coated on to the surface is generally low, not allowing for a therapeutic dose of drug to be retained on the device for periods of time necessary to suppress or alleviate the infection. Second, upon insertion of a device, such as a catheter so treated, it is expected that the surface coating of ionically bound liposomes will be sheared off from the area where the liposomes were intended to reside.
Oloffs et al. 1994; Biomaterials 15:753-758, describe the biocompatibility of silver-coated polyurethane catheters and silver coated Dacron.RTM. material to inhibit infection. These fail to inhibit catheter-related bacterial infection at the infection site (vide supra).
Schierholz, J. et al. 1994; Biomaterials 15:996-1000, disclose the incorporation of antibiotic into an antibiotic releasing silicone ventricle catheter to prevent shunt infection. The antibiotic (rifampicin) was added to the swelling-activated polydimethylsiloxane matrix and would diffuse from the matrix.
Wachol-Drewek et al. 1996, Biomaterials 17:1733-1738, disclose the use of collagen implants of various structures and a gelatin sponge which were placed in antibiotic solutions and allowed to absorb the compounds. They concluded: "If an implant that has a protective effect against wound infections over a period of 24-48 h is required, the materials described here are suitable. However, where treatment in infected areas should ensure antibiotic cover for 5-10 d[days] neither collagen materials immersed in antibiotics nor collagen sponges containing gentamicin are suitable."
Several studies have used photoactivated surface modification in attempts to improve the biocompatibility of biomedical devices. The synthesis of phenylazido-derivatized substances and photochemical surface immobilization of functional groups is presented by Sugawara & Matsuda (J Biomed Mater Res 32:157-164).
The surface modification of silicone by corona discharge for the immobilization of various proteins is disclosed by Okada et al. 1987 (Biomaterials and Clinical Applications, pp. 465-470, Pizzoferrato, A., Marchetti, P. G., Ravglioli, A., & Lee, A.J.C. Elsevier Scientific Publishers, Amsterdam).
Photoreactive surface modification of fabricated devices is described in Matsuda & Inoue 1990 (Trans Am Soc Artif Intern Organs, Poster Session 1, Biomaterials, pp. M161-M164). Nakayama & Matsuda 1992 (ASAIO Journal 38:M421-424) describe the incorporation of heparin, useful as a thromboresistant molecule, within a hydrophilic co-polymer of poly(N,N-dimethylacrylamide)-poly(2-cinnamoylethyl methacrylate) linked to a polyethylene terephthalate surface using a photochemical process; poly(m-azidostyrene) was initially applied to the polyethylene terephalate surface to provide a reactive interface. The procedure produces a cross-linked matrix in which heparin is retained. Sigrist et al. (Optical Eng. (1995) 34:2339-2347) describe surface immobilization of biomolecules by light. Aldenhoff & Koole (J Biomed. Mate. Res. (1995) 29:917-928) describe a method for the photoimmobilization of protein to polyurethane surfaces.
The clinical problem remains that the catheter-related biofilm mediated infection can only be adequately treated by surgical intervention and removal of the bacterial-laden device followed with antibiotic therapy, and surgical re-insertion of a new medical device at a later date. The discomfort to patients and the high costs of these procedures are evident.
The treatment of biofilm-mediated infection on the surface of medical devices is currently extremely difficult, and no medical device or remedy presently available adequately manages liquid-flow conduit line-related infection. Therefore, there is an urgent need for a method of providing adequate doses of antibiotic consistently in targeted fashion on the surface of in-dwelling medical devices so that bacteria are unable to establish a biofilm during the first five to ten, or more days after insertion of the medical device or application of dressings, suture, pins, clips, and other medical devices. There remains a need to develop a practical method for deterring microbial biofilm development on the surface of catheters and other in-dwelling medical devices in contact with tissue, so that device-related infections are significantly reduced.
It is an object of the present invention to provide a biocompatible hydrogel matrix, containing liposomal antibiotic that can be coated onto the surface of in-dwelling biomedical devices. It is a further objective to provide methods for formulating such hydrogel matrix compositions; and it is a still further objective to provide methods to co-valently attach said hydrogel to the surface of substrates such as catheters. The type of drug incorporated into the hydrogel formulation is not restricted to any single antibiotic, or combination of one or more of these. Similarly, the hydrogel composition might comprise a variety of active agents including antibiotics, hormones, growth factors and other factors that are beneficial for the condition under management, in accordance with sound medical judgement.